Researchers in the Departments of Anesthesia and Psychiatry, at the University of Washington St Louis performed a prospective, randomized blinded study on 40 patients with treatment-resistant depression (TRD). While their inclusion criteria required two failed complete attempts at therapy, the average number of failed treatments for the patients averaged eight. The number of 40 patients was chosen based on previous studies done with ketamine (see below).

The theory behind the research comes from the fact that depression is partially mediated by N-methyl-D-aspartate (NMDA) receptors in the brain, and the researchers surmised that if NMDA receptors could be blocked, there might be a reduction in depressive symptoms. Previous research has shown that exposure to small doses of ketamine has had the effect of ameliorating depressive symptoms. The side effects of ketamine exposure (hallucinations, delusions) have made this treatment less than ideal. The thought was that, although nitrous oxide has some side effects, these would wear off in minutes due to its rapid washout from the body. So, with minimal side effects, the postulate was that exposure to nitrous oxide would potentially have a positive effect in treating TRD.

After informed consent, patients were randomized to receive an hour of exposure to 50% nitrous oxide in oxygen or 50% nitrogen in oxygen, administered by anesthesia circuit and monitored using ASA guidelines. The patients were all white, 60% female, and had previous exposure to a wide variety of anti-depressant drugs. Both patients and researchers conducting the depression evaluations were blinded to the identity of the inhaled gas. The patients were then allowed to recover away from the researchers conducting the depression assessment. Two and twenty-four hours after exposure, patients completed a standardized assessment of depression (the Hamilton Rating Scale for Depression), which was then repeated after a week. Inclusion criteria for the study required a score above 18 on the 56-point scale. Fifty percent nitrous oxide was chosen as the exposure level based on its proven safety used in millions of both dental surgeries as well as labor analgesia. The depression scale was completed two hours after exposure (or not) to the nitrous oxide to allow for the euphoric effects to wear off and, failing that, repeated after a week, ensuring that there was no possible exposure to nitrous oxide in the 7 days prior to re-testing.

Results

Both sets of patients showed a reduction of depressive symptoms, the nitrogen group by approximately 2 points at 2 and 24 hours, while the nitrous oxide group showed a reduction of approximately 5 points at both measurement points. Four times as many patients in the nitrous oxide group vs. the nitrogen group showed a reduction in their depressive symptoms by greater than 50%. Approximately 1 in 6 patients in the nitrous oxide group (15%) and none in the nitrogen group showed complete remission in their symptoms.

Ten patients in each group were assessed at 1 week following exposure (as a baseline before the second exposure). While the results did not reach statistical significance (p= 0.74), the treatment group had absolute improvement in their depression assessments vs. the placebo group.

Side-effects

The most common side effect of exposure to nitrous oxide was nausea and vomiting, appearing in approximately 15% of those exposed (vs. none in the placebo group), headache (occurring in 10% of both groups) numbness, parasthesia or anxiety (10 % in the study group, none in the placebo group) and dizziness or light-headedness (5% in study group vs. 10 in placebo group).

Discussion

While these results are preliminary, they certainly show promise for further study. There are several limitations to this investigation. While the subjects were not asked, some might have been aware that they were being exposed to nitrous oxide because of its slightly sweet smell and euphoric effects. While the researchers went to pains to only test the patients at two hours after exposure, there is always the possibility that the euphoric effects (while unlikely) might have biased the depression assessment scores. Even at 24 hours, there is the possibility that nitrous oxide may have masked or “covered up” depression scores.

Certainly, the reduction in depression scores, similar to ketamine, validates the theory that NMDA receptors are involved in the mechanism of depression.

One issue that was not studied was the effect on Vitamin B12. Many patients are exposed to nitrous oxide for longer periods under anesthesia without ill-effect, but the frequency of exposure and the effect on Vitamin B12 metabolism has not been effectively studied.

Conclusion

Exposure to nitrous oxide has a definite improvement in depression symptoms measured by one scale in treatment-resistant depressed patients. The study needs to be performed in larger groups, and the percentage of nitrous oxide having this effect needs to be studied, both to find the optimal dose for the effect, as well as to minimize side-effects which are, admittedly, short-lived.